Early-onset (DYT1) torsion dystonia is a devastating non-degenerative neurological movement disorder caused by autosomal dominant inheritance of a glutamic acid deletion in the protein torsinA (TOR1A), frequently referred to as the ?GAG or ?E mutation because of the deleted codon or amino acid. The CNS abnormalities underlying dystonia are poorly understood, with functional imaging and clinical electrophysiology studies suggesting abnormalities in a range of structures throughout the motor circuit. More specific insight should come from understanding the responsible genetic change. TorsinA is a member of the AAA+ family of ATPases found in the lumen of the endoplasmic reticulum and nuclear envelope. It is expressed ubiquitously, and the known failure of ?E-mutant enzyme to rescue torsinA knock-out animals from perinatal lethality suggests that this mutant lacks whatever essential activity torsinA normally provides. However, the specific functions ascribed to torsinA vary widely and are not well defined despite the fact that it has been more than a decade since the protein was first described and linked to dystonia. This lack of insight is creating a major roadblock in efforts to develop targeted and effective treatments for dystonia. We propose a set of experiments aimed at clarifying the cellular function and disease-linked dysfunction of torsinA in cultured human cells. We will build on preliminary data showing that the distribution of torsinA within the endomembrane system is regulated and likely to play an important role in defining the enzyme's activity.
The specific aims of the project are (1) to define the basis for association of torsinA with the endoplasmic reticulum membrane and its distribution and retention in this organelle, (2) to delineate the mechanism by which an interacting protein LULL1 (TOR1IP2) controls the distribution of torsinA between the endoplasmic reticulum and nuclear envelope, (3) to explore the effects of torsinA on known substrates using cellular and biochemical assays, and (4) to determine how disease-associated mutations affect torsinA structure and function. These studies are broadly relevant because they address potentially novel means of regulating the localization of proteins within cells, while also providing insight into the etiology of DYT1 dystonia.

Public Health Relevance

Early-onset (DYT1) torsion dystonia is a devastating non-degenerative neurological movement disorder caused by autosomal dominant inheritance of a deletion in the protein torsinA. The function of torsinA is unknown. Our studies will define the cellular role and regulation of this important enzyme, thus opening the door to the development of targeted therapeutics for dystonia, which after Parkinson's disease and tremor is the is the third most common movement disorder in the US.